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      Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy

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          Abstract

          Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewis a, Lewis b, and sialyl Lewis a) and type II (H2, Lewis x, Lewis y, and sialyl Lewis x) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor-overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, endothelial to mesenchymal transition, endothelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients.

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          Most cited references125

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          Dendritic Cells and Cancer Immunity.

          Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors. Bypassing suppressive pathways or directly activating DCs can unleash a T-cell response, and although clinical efficacy has proven elusive, therapeutic targeting of DCs continues to hold translational potential in combinatorial approaches.
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            Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.

            Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. Here, we demonstrate that ICAM-3 expressed by resting T cells is important in this first contact with DC. We discovered that instead of the common ICAM-3 receptors LFA-1 and alphaDbeta2, a novel DC-specific C-type lectin, DC-SIGN, binds ICAM-3 with high affinity. DC-SIGN, which is abundantly expressed by DC both in vitro and in vivo, mediates transient adhesion with T cells. Since antibodies against DC-SIGN inhibit DC-induced proliferation of resting T cells, our findings predict that DC-SIGN enables T cell receptor engagement by stabilization of the DC-T cell contact zone.
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              Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp

              Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/502706
                URI : http://frontiersin.org/people/u/209933
                URI : http://frontiersin.org/people/u/46631
                URI : http://frontiersin.org/people/u/202091
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                23 February 2018
                2018
                : 8
                : 39
                Affiliations
                [1] 1Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center , Amsterdam, Netherlands
                Author notes

                Edited by: Leonardo Freire-de-Lima, Universidade Federal do Rio de Janeiro, Brazil

                Reviewed by: Usha Nagarajan, SASTRA University, India; Tony Lefebvre, Lille University of Science and Technology, France; Andreia Machado Leopoldino, University of São Paulo, Brazil

                *Correspondence: Sandra J. van Vliet, s.vanvliet@ 123456vumc.nl

                Specialty section: This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00039
                5829055
                29527514
                9342ea68-ea34-481d-a32b-feaf530e6377
                Copyright © 2018 Blanas, Sahasrabudhe, Rodríguez, van Kooyk and van Vliet.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 November 2017
                : 05 February 2018
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 153, Pages: 14, Words: 11680
                Funding
                Funded by: KWF Kankerbestrijding 10.13039/501100004622
                Award ID: 6779-VU-2014
                Funded by: H2020 Marie Skłodowska-Curie Actions 10.13039/100010665
                Award ID: GlyCoCan project, 676421; Immunoshape project, 642870
                Funded by: FP7 Ideas: European Research Council 10.13039/100011199
                Award ID: ERC Advanced grant, Glycotreat, 339977
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                cancer,glycosylation,fucosylation,fucosyltransferases,lewis antigens
                Oncology & Radiotherapy
                cancer, glycosylation, fucosylation, fucosyltransferases, lewis antigens

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